Metabolomic investigation of cholestasis in a rat model using ultra-performance liquid chromatography/tandem mass spectrometry
Metabolomic investigation of cholestasis in a rat model using ultra-performance liquid chromatography/tandem mass spectrometry
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DOI：
10.1002/rcm.5072
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发表时间：
2011-07-15
影响因子：
2
通讯作者：
Komuro, Setsuko
中科院分区：
文献类型：
--
作者：
Aoki, Masayo;Konya, Yutaka;Komuro, Setsuko
代谢组学研究内源性代谢物浓度的变化，这可能反映各种疾病状态以及对环境，治疗或遗传干预的全身反应。在本研究中，我们应用代谢组学方法监测血浆和尿液代谢物的动态变化，并将EHBR高胆红素血症大鼠（EHBR，胆汁淤积的动物模型）中的这些代谢物谱与EHBR的亲本品系- Sprague-Dawley（SD）大鼠中的代谢物谱进行比较，以从病理生理学上表征胆汁淤积。使用基于超高效液相色谱/串联质谱的分析方法测定代谢物水平。在血浆和尿液中检测到超过250种代谢产物，EHBR的代谢产物谱与SD大鼠不同。EHBR尿中抗氧化和细胞保护代谢产物牛磺酸和亚牛磺酸水平显著升高。EHBR患者血浆和尿液中多种胆汁酸水平也升高，但升高的程度取决于特定的胆汁酸。细胞保护性熊去氧胆酸及其结合物的水平显著升高，而细胞毒性鹅去氧胆酸的水平保持不变，表明胆汁酸的平衡发生了变化，导致毒性降低。在EHBR中，胆汁排泄减少导致对有害化合物（包括一些内源性代谢物）的全身暴露增加。我们的代谢组学数据表明EHBR中存在补偿胆汁淤积相关损伤的机制。版权所有（C）2011约翰威利父子有限公司
Metabolomics follows the changes in concentrations of endogenous metabolites, which may reflect various disease states as well as systemic responses to environmental, therapeutic, or genetic interventions. In this study, we applied metabolomic approaches to monitor dynamic changes in plasma and urine metabolites, and compared these metabolite profiles in Eisai hyperbilirubinemic rats (EHBR, an animal model of cholestasis) with those in the parent strain of EHBR - Sprague-Dawley (SD) rats - in order to characterize cholestasis pathophysiologically. Ultra-performance liquid chromatography/tandem mass spectrometry-based analytical methods were used to assay metabolite levels. More than 250 metabolites were detected in both plasma and urine, and metabolite profiles of EHBR differed from those of SD rats. The levels of antioxidative and cytoprotective metabolites, taurine and hypotaurine, were markedly increased in urine of EHBR. The levels of many bile acids were also elevated in plasma and urine of EHBR, but the extent of elevation depended on the particular bile acid. The levels of cytoprotective ursodeoxycholic acid and its conjugates were markedly elevated, while that of cytotoxic chenodeoxycholic acid remained unchanged, suggesting the balance of bile acids had shifted resulting in decreased toxicity. In EHBR, reduced biliary excretion leads to increased systemic exposure to harmful compounds including some endogenous metabolites. Our metabolomic data suggest that mechanisms exist in EHBR that compensate for cholestasis-related damage. Copyright (C) 2011 John Wiley & Sons, Ltd.